The physiology of alternative splicing.
Journal
Nature reviews. Molecular cell biology
ISSN: 1471-0080
Titre abrégé: Nat Rev Mol Cell Biol
Pays: England
ID NLM: 100962782
Informations de publication
Date de publication:
04 2023
04 2023
Historique:
accepted:
15
09
2022
medline:
28
3
2023
pubmed:
14
10
2022
entrez:
13
10
2022
Statut:
ppublish
Résumé
Alternative splicing is a substantial contributor to the high complexity of transcriptomes of multicellular eukaryotes. In this Review, we discuss the accumulated evidence that most of this complexity is reflected at the protein level and fundamentally shapes the physiology and pathology of organisms. This notion is supported not only by genome-wide analyses but, mainly, by detailed studies showing that global and gene-specific modulations of alternative splicing regulate highly diverse processes such as tissue-specific and species-specific cell differentiation, thermal regulation, neuron self-avoidance, infrared sensing, the Warburg effect, maintenance of telomere length, cancer and autism spectrum disorders (ASD). We also discuss how mastering the control of alternative splicing paved the way to clinically approved therapies for hereditary diseases.
Identifiants
pubmed: 36229538
doi: 10.1038/s41580-022-00545-z
pii: 10.1038/s41580-022-00545-z
doi:
Types de publication
Journal Article
Review
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
242-254Informations de copyright
© 2022. Springer Nature Limited.
Références
Chow, L. T., Gelinas, R. E., Broker, T. R. & Roberts, R. J. An amazing sequence arrangement at the 5′ ends of adenovirus 2 messenger RNA. Cell 12, 1–8 (1977).
pubmed: 902310
doi: 10.1016/0092-8674(77)90180-5
Berget, S. M., Moore, C. & Sharp, P. A. Spliced segments at the 5′ terminus of adenovirus 2 late mRNA. Proc. Natl Acad. Sci. USA 74, 3171–3175 (1977).
pubmed: 269380
pmcid: 431482
doi: 10.1073/pnas.74.8.3171
Gilbert, W. Why genes in pieces? Nature 271, 501 (1978).
pubmed: 622185
doi: 10.1038/271501a0
Khan, M. R., Wellinger, R. J. & Laurent, B. Exploring the alternative splicing of long noncoding RNAs. Trends Genet. 37, 695–698 (2021).
pubmed: 33892960
doi: 10.1016/j.tig.2021.03.010
Rogers, S. O. Integrated evolution of ribosomal RNAs, introns, and intron nurseries. Genetica 147, 103–119 (2019).
pubmed: 30578455
doi: 10.1007/s10709-018-0050-y
Sekulovski, S. et al. Assembly defects of human tRNA splicing endonuclease contribute to impaired pre-tRNA processing in pontocerebellar hypoplasia. Nat. Commun. 12, 5610 (2021).
pubmed: 34584079
pmcid: 8479045
doi: 10.1038/s41467-021-25870-3
Kearse, M. G. & Wilusz, J. E. Non-AUG translation: a new start for protein synthesis in eukaryotes. Genes Dev. 31, 1717–1731 (2017).
pubmed: 28982758
pmcid: 5666671
doi: 10.1101/gad.305250.117
Smith, C. W. & Valcárcel, J. Alternative pre-mRNA splicing: the logic of combinatorial control. Trends Biochem. Sci. 25, 381–388 (2000).
pubmed: 10916158
doi: 10.1016/S0968-0004(00)01604-2
Kastner, B., Will, C. L., Stark, H. & Lührmann, R. Structural insights into nuclear pre-mRNA splicing in higher eukaryotes. Cold Spring Harb. Perspect. Biol. 11, a032417 (2019).
pubmed: 30765414
pmcid: 6824238
doi: 10.1101/cshperspect.a032417
Licatalosi, D. D. & Darnell, R. B. RNA processing and its regulation: global insights into biological networks. Nat. Rev. Genet. 11, 75–87 (2010).
pubmed: 20019688
pmcid: 3229837
doi: 10.1038/nrg2673
Irimia, M. & Blencowe, B. J. Alternative splicing: decoding an expansive regulatory layer. Curr. Opin. Cell Biol. 24, 323–332 (2012).
pubmed: 22465326
doi: 10.1016/j.ceb.2012.03.005
Kornblihtt, A. R. et al. Alternative splicing: a pivotal step between eukaryotic transcription and translation. Nat. Rev. Mol. Cell Biol. 14, 153–165 (2013).
pubmed: 23385723
doi: 10.1038/nrm3525
Fu, X.-D. & Ares, M. Context-dependent control of alternative splicing by RNA-binding proteins. Nat. Rev. Genet. 15, 689–701 (2014).
pubmed: 25112293
pmcid: 4440546
doi: 10.1038/nrg3778
Baralle, F. E. & Giudice, J. Alternative splicing as a regulator of development and tissue identity. Nat. Rev. Mol. Cell Biol. 18, 437–451 (2017).
pubmed: 28488700
pmcid: 6839889
doi: 10.1038/nrm.2017.27
Ule, J. & Blencowe, B. J. Alternative splicing regulatory networks: functions, mechanisms, and evolution. Mol. Cell 76, 329–345 (2019).
pubmed: 31626751
doi: 10.1016/j.molcel.2019.09.017
Shenasa, H. & Hertel, K. J. Combinatorial regulation of alternative splicing. Biochim. Biophys. Acta Gene Regul. Mech. 1862, 194392 (2019).
pubmed: 31276857
pmcid: 9640221
doi: 10.1016/j.bbagrm.2019.06.003
Gordon, J. M., Phizicky, D. V. & Neugebauer, K. M. Nuclear mechanisms of gene expression control: pre-mRNA splicing as a life or death decision.Curr. Opin. Genet. Dev. 67, 67–76 (2021).
pubmed: 33291060
doi: 10.1016/j.gde.2020.11.002
Buratti, E., Baralle, M. & Baralle, F. E. From single splicing events to thousands: the ambiguous step forward in splicing research. Brief. Funct. Genomics 12, 3–12 (2013).
pubmed: 23165350
doi: 10.1093/bfgp/els048
Pan, Q., Shai, O., Lee, L. J., Frey, B. J. & Blencowe, B. J. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat. Genet. 40, 1413–1415 (2008).
pubmed: 18978789
doi: 10.1038/ng.259
Wang, E. T. et al. Alternative isoform regulation in human tissue transcriptomes. Nature 456, 470–476 (2008).
pubmed: 18978772
pmcid: 2593745
doi: 10.1038/nature07509
Saldi, T., Riemondy, K., Erickson, B. & Bentley, D. L. Alternative RNA structures formed during transcription depend on elongation rate and modify RNA processing. Mol. Cell 81, 1789–1801.e5 (2021).
pubmed: 33631106
pmcid: 8052309
doi: 10.1016/j.molcel.2021.01.040
Luco, R. F., Allo, M., Schor, I. E., Kornblihtt, A. R. & Misteli, T. Epigenetics in alternative pre-mRNA splicing. Cell 144, 16–26 (2011).
pubmed: 21215366
pmcid: 3038581
doi: 10.1016/j.cell.2010.11.056
de la Mata, M. et al. A slow RNA polymerase II affects alternative splicing in vivo. Mol. Cell 12, 525–532 (2003).
pubmed: 14536091
doi: 10.1016/j.molcel.2003.08.001
Dujardin, G. et al. How slow RNA polymerase II elongation favors alternative exon skipping. Mol. Cell 54, 683–690 (2014).
pubmed: 24793692
doi: 10.1016/j.molcel.2014.03.044
Fong, N. et al. Pre-mRNA splicing is facilitated by an optimal RNA polymerase II elongation rate. Genes Dev. 28, 2663–2676 (2014).
pubmed: 25452276
pmcid: 4248296
doi: 10.1101/gad.252106.114
Maslon, M. M. et al. A slow transcription rate causes embryonic lethality and perturbs kinetic coupling of neuronal genes. EMBO J. 38, e101244 (2019).
pubmed: 30988016
pmcid: 6484407
doi: 10.15252/embj.2018101244
Schor, I. E., Rascovan, N., Pelisch, F., Alló, M. & Kornblihtt, A. R. Neuronal cell depolarization induces intragenic chromatin modifications affecting NCAM alternative splicing. Proc. Natl Acad. Sci. USA 106, 4325–4330 (2009).
pubmed: 19251664
pmcid: 2657401
doi: 10.1073/pnas.0810666106
Alló, M. et al. Control of alternative splicing through siRNA-mediated transcriptional gene silencing. Nat. Struct. Mol. Biol. 16, 717–724 (2009).
pubmed: 19543290
doi: 10.1038/nsmb.1620
Schor, I. E., Fiszbein, A., Petrillo, E. & Kornblihtt, A. R. Intragenic epigenetic changes modulate NCAM alternative splicing in neuronal differentiation. EMBO J. 32, 2264–2274 (2013).
pubmed: 23892457
pmcid: 3746202
doi: 10.1038/emboj.2013.167
Segelle, A. et al. Histone marks regulate the epithelial-to-mesenchymal transition via alternative splicing. Cell Rep. 38, 110357 (2022).
pubmed: 35172149
doi: 10.1016/j.celrep.2022.110357
Eling, N., Morgan, M. D. & Marioni, J. C. Challenges in measuring and understanding biological noise. Nat. Rev. Genet. 20, 536–548 (2019).
pubmed: 31114032
pmcid: 7611518
doi: 10.1038/s41576-019-0130-6
Tress, M. L., Abascal, F. & Valencia, A. Most alternative isoforms are not functionally important. Trends Biochem. Sci. 42, 98–110 (2017).
pubmed: 27712956
doi: 10.1016/j.tibs.2016.08.008
Rodriguez, J. M., Pozo, F., di Domenico, T., Vazquez, J. & Tress, M. L. An analysis of tissue-specific alternative splicing at the protein level. PLoS Comput. Biol. 16, e1008287 (2020).
pubmed: 33017396
pmcid: 7561204
doi: 10.1371/journal.pcbi.1008287
Pozo, F. et al. Assessing the functional relevance of splice isoforms. NAR Genomics Bioinform 3, lqab044 (2021).
doi: 10.1093/nargab/lqab044
Blencowe, B. J. The relationship between alternative splicing and proteomic complexity. Trends Biochem. Sci. 42, 407–408 (2017).
pubmed: 28483376
doi: 10.1016/j.tibs.2017.04.001
Ingolia, N. T. Ribosome footprint profiling of translation throughout the genome. Cell 165, 22–33 (2016).
pubmed: 27015305
pmcid: 4917602
doi: 10.1016/j.cell.2016.02.066
Weatheritt, R. J., Sterne-Weiler, T. & Blencowe, B. J. The ribosome-engaged landscape of alternative splicing. Nat. Struct. Mol. Biol. 23, 1117–1123 (2016).
pubmed: 27820807
pmcid: 5295628
doi: 10.1038/nsmb.3317
Kurosaki, T. & Maquat, L. E. Nonsense-mediated mRNA decay in humans at a glance. J. Cell Sci. 129, 461–467 (2016).
pubmed: 26787741
pmcid: 4760306
Floor, S. N. & Doudna, J. A. Tunable protein synthesis by transcript isoforms in human cells. eLife 5, e10921 (2016).
pubmed: 26735365
pmcid: 4764583
doi: 10.7554/eLife.10921
Sterne-Weiler, T. et al. Frac-seq reveals isoform-specific recruitment to polyribosomes. Genome Res. 23, 1615–1623 (2013).
pubmed: 23783272
pmcid: 3787259
doi: 10.1101/gr.148585.112
Xing, Y. & Lee, C. Alternative splicing and RNA selection pressure — evolutionary consequences for eukaryotic genomes. Nat. Rev. Genet. 7, 499–509 (2006).
pubmed: 16770337
doi: 10.1038/nrg1896
Bell, L. R., Horabin, J. I., Schedl, P. & Cline, T. W. Positive autoregulation of Sex-lethal by alternative splicing maintains the female determined state in Drosophila. Cell 65, 229–239 (1991).
pubmed: 2015624
doi: 10.1016/0092-8674(91)90157-T
Gracheva, E. O. et al. Ganglion-specific splicing of TRPV1 underlies infrared sensation in vampire bats. Nature 476, 88–91 (2011).
pubmed: 21814281
pmcid: 3535012
doi: 10.1038/nature10245
Amara, S. G., Jonas, V., Rosenfeld, M. G., Ong, E. S. & Evans, R. M. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature 298, 240–244 (1982).
pubmed: 6283379
doi: 10.1038/298240a0
Peterson, M. L. Immunoglobulin heavy chain gene regulation through polyadenylation and splicing competition. Wiley Interdiscip. Rev. RNA 2, 92–105 (2011).
pubmed: 21956971
doi: 10.1002/wrna.36
Hattori, D. et al. Robust discrimination between self and non-self neurites requires thousands of Dscam1 isoforms. Nature 461, 644–648 (2009).
pubmed: 19794492
pmcid: 2836808
doi: 10.1038/nature08431
Emery, A. & Swanstrom, R. HIV-1: to splice or not to splice, that is the question. Viruses 13, 181–190 (2021).
pubmed: 33530363
pmcid: 7912102
doi: 10.3390/v13020181
Liu, Y., Beyer, A. & Aebersold, R. On the dependency of cellular protein levels on mRNA abundance. Cell 165, 535–550 (2016).
pubmed: 27104977
doi: 10.1016/j.cell.2016.03.014
El Marabti, E. & Younis, I. The cancer spliceome: reprograming of alternative splicing in cancer. Front. Mol. Biosci. 5, 80 (2018).
pubmed: 30246013
pmcid: 6137424
doi: 10.3389/fmolb.2018.00080
Bangru, S. et al. Alternative splicing rewires Hippo signaling pathway in hepatocytes to promote liver regeneration. Nat. Struct. Mol. Biol. 25, 928–939 (2018).
pubmed: 30250226
pmcid: 6173981
doi: 10.1038/s41594-018-0129-2
Jensen, M. A., Wilkinson, J. E. & Krainer, A. R. Splicing factor SRSF6 promotes hyperplasia of sensitized skin. Nat. Struct. Mol. Biol. 21, 189–197 (2014).
pubmed: 24440982
pmcid: 4118672
doi: 10.1038/nsmb.2756
Anczuków, O. & Krainer, A. R. Splicing-factor alterations in cancers. RNA 22, 1285–1301 (2016).
pubmed: 27530828
pmcid: 4986885
doi: 10.1261/rna.057919.116
Cherry, S. & Lynch, K. W. Alternative splicing and cancer: insights, opportunities, and challenges from an expanding view of the transcriptome. Genes Dev. 34, 1005–1016 (2020).
pubmed: 32747477
pmcid: 7397854
doi: 10.1101/gad.338962.120
Gurnari, C., Pagliuca, S. & Visconte, V. Alternative splicing in myeloid malignancies. Biomedicines 9, 1844–1851 (2021).
pubmed: 34944660
pmcid: 8698609
doi: 10.3390/biomedicines9121844
Karni, R. et al. The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat. Struct. Mol. Biol. 14, 185–193 (2007).
pubmed: 17310252
pmcid: 4595851
doi: 10.1038/nsmb1209
Das, S., Anczuków, O., Akerman, M. & Krainer, A. R. Oncogenic splicing factor SRSF1 is a critical transcriptional target of MYC. Cell Rep. 1, 110–117 (2012).
pubmed: 22545246
pmcid: 3334311
doi: 10.1016/j.celrep.2011.12.001
Rahman, M. A., Lin, K.-T., Bradley, R. K., Abdel-Wahab, O. & Krainer, A. R. Recurrent SRSF2 mutations in MDS affect both splicing and NMD. Genes Dev. 34, 413–427 (2020).
pubmed: 32001512
pmcid: 7050488
doi: 10.1101/gad.332270.119
Papasaikas, P., Tejedor, J. R., Vigevani, L. & Valcárcel, J. Functional splicing network reveals extensive regulatory potential of the core spliceosomal machinery. Mol. Cell 57, 7–22 (2015).
pubmed: 25482510
doi: 10.1016/j.molcel.2014.10.030
Saltzman, A. L., Pan, Q. & Blencowe, B. J. Regulation of alternative splicing by the core spliceosomal machinery. Genes Dev. 25, 373–384 (2011).
pubmed: 21325135
pmcid: 3042160
doi: 10.1101/gad.2004811
Pleiss, J. A., Whitworth, G. B., Bergkessel, M. & Guthrie, C. Transcript specificity in yeast pre-mRNA splicing revealed by mutations in core spliceosomal components. PLoS Biol. 5, e90 (2007).
pubmed: 17388687
pmcid: 1831718
doi: 10.1371/journal.pbio.0050090
Radzisheuskaya, A. et al. PRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemia. Nat. Struct. Mol. Biol. 26, 992–1012 (2019).
doi: 10.1038/s41594-019-0313-z
Braun, C. J. et al. Coordinated splicing of regulatory detained introns within oncogenic transcripts creates an exploitable vulnerability in malignant glioma. Cancer Cell 32, 411–426.e11 (2017).
pubmed: 28966034
pmcid: 5929990
doi: 10.1016/j.ccell.2017.08.018
Sanford, J. R., Gray, N. K., Beckmann, K. & Cáceres, J. F. A novel role for shuttling SR proteins in mRNA translation. Genes Dev. 18, 755–768 (2004).
pubmed: 15082528
pmcid: 387416
doi: 10.1101/gad.286404
Haward, F. et al. Nucleo-cytoplasmic shuttling of splicing factor SRSF1 is required for development and cilia function. eLife 10, e65104 (2021).
pubmed: 34338635
pmcid: 8352595
doi: 10.7554/eLife.65104
Munkley, J. et al. Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer. eLife 8, e47678 (2019).
pubmed: 31478829
pmcid: 6788855
doi: 10.7554/eLife.47678
Irimia, M. et al. A highly conserved program of neuronal microexons is misregulated in autistic brains. Cell 159, 1511–1523 (2014).
pubmed: 25525873
pmcid: 4390143
doi: 10.1016/j.cell.2014.11.035
Ellis, J. D. et al. Tissue-specific alternative splicing remodels protein–protein interaction networks. Mol. Cell 46, 884–892 (2012).
pubmed: 22749401
doi: 10.1016/j.molcel.2012.05.037
Buljan, M. et al. Tissue-specific splicing of disordered segments that embed binding motifs rewires protein interaction networks. Mol. Cell 46, 871–883 (2012).
pubmed: 22749400
pmcid: 3437557
doi: 10.1016/j.molcel.2012.05.039
Gonatopoulos-Pournatzis, T. et al. Autism-misregulated eIF4G microexons control synaptic translation and higher order cognitive functions. Mol. Cell 77, 1176–1192.e16 (2020).
pubmed: 31999954
doi: 10.1016/j.molcel.2020.01.006
Parras, A. et al. Autism-like phenotype and risk gene mRNA deadenylation by CPEB4 mis-splicing. Nature 560, 441–446 (2018).
pubmed: 30111840
pmcid: 6217926
doi: 10.1038/s41586-018-0423-5
Sharon, G. et al. Human gut microbiota from autism spectrum disorder promote behavioral symptoms in mice. Cell 177, 1600–1618 (2019).
pubmed: 31150625
pmcid: 6993574
doi: 10.1016/j.cell.2019.05.004
Haltenhof, T. et al. A conserved kinase-based body-temperature sensor globally controls alternative splicing and gene expression. Mol. Cell 78, 57–69 (2020).
pubmed: 32059760
doi: 10.1016/j.molcel.2020.01.028
Martin Anduaga, A. et al. Thermosensitive alternative splicing senses and mediates temperature adaptation in Drosophila. eLife 8, e44642 (2019).
pubmed: 31702556
pmcid: 6890466
doi: 10.7554/eLife.44642
Barbosa-Morais, N. L. et al. The evolutionary landscape of alternative splicing in vertebrate species. Science 338, 1587–1593 (2012).
pubmed: 23258890
doi: 10.1126/science.1230612
Merkin, J., Russell, C., Chen, P. & Burge, C. B. Evolutionary dynamics of gene and isoform regulation in mammalian tissues. Science 338, 1593–1599 (2012).
pubmed: 23258891
pmcid: 3568499
doi: 10.1126/science.1228186
Gueroussov, S. et al. An alternative splicing event amplifies evolutionary differences between vertebrates. Science 349, 868–873 (2015).
pubmed: 26293963
doi: 10.1126/science.aaa8381
Guo, W. et al. RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing. Nat. Med. 18, 766–773 (2012).
pubmed: 22466703
pmcid: 3569865
doi: 10.1038/nm.2693
Murphy, P. A. et al. Alternative RNA splicing in the endothelium mediated in part by Rbfox2 regulates the arterial response to low flow. eLife 7, e29494 (2018).
pubmed: 29293084
pmcid: 5771670
doi: 10.7554/eLife.29494
Vernia, S. et al. An alternative splicing program promotes adipose tissue thermogenesis. eLife 5, e17672 (2016).
pubmed: 27635635
pmcid: 5026472
doi: 10.7554/eLife.17672
Marcheva, B. et al. A role for alternative splicing in circadian control of exocytosis and glucose homeostasis. Genes Dev. 34, 1089–1105 (2020).
pubmed: 32616519
pmcid: 7397853
doi: 10.1101/gad.338178.120
Ha, K. C. H., Sterne-Weiler, T., Morris, Q., Weatheritt, R. J. & Blencowe, B. J. Differential contribution of transcriptomic regulatory layers in the definition of neuronal identity. Nat. Commun. 12, 335 (2021).
pubmed: 33436550
pmcid: 7804943
doi: 10.1038/s41467-020-20483-8
Leff, S. E., Evans, R. M. & Rosenfeld, M. G. Splice commitment dictates neuron-specific alternative RNA processing in calcitonin/CGRP gene expression. Cell 48, 517–524 (1987).
pubmed: 2879637
doi: 10.1016/0092-8674(87)90202-9
Schmucker, D. et al. Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity. Cell 101, 671–684 (2000).
pubmed: 10892653
doi: 10.1016/S0092-8674(00)80878-8
Graveley, B. R. Mutually exclusive splicing of the insect Dscam pre-mRNA directed by competing intronic RNA secondary structures. Cell 123, 65–73 (2005).
pubmed: 16213213
pmcid: 2366815
doi: 10.1016/j.cell.2005.07.028
Goodman, K. M. et al. How clustered protocadherin binding specificity is tuned for neuronal self-/nonself-recognition. eLife 11, e72416 (2022).
pubmed: 35253643
pmcid: 8901172
doi: 10.7554/eLife.72416
Penev, A. et al. Alternative splicing is a developmental switch for hTERT expression. Mol. Cell 81, 2349–2360.e6 (2021).
pubmed: 33852895
pmcid: 8943697
doi: 10.1016/j.molcel.2021.03.033
Fiszbein, A. et al. Alternative splicing of G9a regulates neuronal differentiation. Cell Rep. 14, 2797–2808 (2016).
pubmed: 26997278
doi: 10.1016/j.celrep.2016.02.063
Gabut, M. et al. An alternative splicing switch regulates embryonic stem cell pluripotency and reprogramming. Cell 147, 132–146 (2011).
pubmed: 21924763
doi: 10.1016/j.cell.2011.08.023
Han, H. et al. MBNL proteins repress ES-cell-specific alternative splicing and reprogramming. Nature 498, 241–245 (2013).
pubmed: 23739326
pmcid: 3933998
doi: 10.1038/nature12270
Choksi, A. et al. Tumor suppressor SMAR1 regulates PKM alternative splicing by HDAC6-mediated deacetylation of PTBP1. Cancer Metab. 9, 16–21 (2021).
pubmed: 33863392
pmcid: 8052847
doi: 10.1186/s40170-021-00252-x
David, C. J., Chen, M., Assanah, M., Canoll, P. & Manley, J. L. hnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 463, 364–368 (2010).
pubmed: 20010808
doi: 10.1038/nature08697
Mirtschink, P. et al. HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease. Nature 522, 444–449 (2015).
pubmed: 26083752
pmcid: 4783869
doi: 10.1038/nature14508
Li, G. et al. Exclusion of alternative exon 33 of Ca
pubmed: 28490495
pmcid: 5448171
Sebastian, S. et al. Tissue-specific splicing of a ubiquitously expressed transcription factor is essential for muscle differentiation. Genes Dev. 27, 1247–1259 (2013).
pubmed: 23723416
pmcid: 3690398
doi: 10.1101/gad.215400.113
Scharner, J. & Aznarez, I. Clinical applications of single-stranded oligonucleotides: current landscape of approved and in-development therapeutics. Mol. Ther. 29, 540–554 (2021).
pubmed: 33359792
doi: 10.1016/j.ymthe.2020.12.022
Monani, U. R. The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn
pubmed: 10655541
doi: 10.1093/hmg/9.3.333
Singh, N. K., Singh, N. N., Androphy, E. J. & Singh, R. N. Splicing of a critical exon of human Survival Motor Neuron is regulated by a unique silencer element located in the last intron. Mol. Cell. Biol. 26, 1333–1346 (2006).
pubmed: 16449646
pmcid: 1367187
doi: 10.1128/MCB.26.4.1333-1346.2006
Hua, Y., Vickers, T. A., Okunola, H. L., Bennett, C. F. & Krainer, A. R. Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice. Am. J. Hum. Genet. 82, 834–848 (2008).
pubmed: 18371932
pmcid: 2427210
doi: 10.1016/j.ajhg.2008.01.014
Hua, Y. et al. Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 478, 123–126 (2011).
pubmed: 21979052
pmcid: 3191865
doi: 10.1038/nature10485
Hua, Y. et al. Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models. Genes Dev. 29, 288–297 (2015).
pubmed: 25583329
pmcid: 4318145
doi: 10.1101/gad.256644.114
Chiriboga, C. A. et al. Results from a phase 1 study of nusinersen (ISIS-SMN
pubmed: 26865511
pmcid: 4782111
doi: 10.1212/WNL.0000000000002445
Rigo, F. et al. Pharmacology of a central nervous system delivered 2′-O-methoxyethyl-modified survival of motor neuron splicing oligonucleotide in mice and nonhuman primates. J. Pharmacol. Exp. Ther. 350, 46–55 (2014).
pubmed: 24784568
pmcid: 4056267
doi: 10.1124/jpet.113.212407
Marasco, L. E. et al. Counteracting chromatin effects of a splicing-correcting antisense oligonucleotide improves its therapeutic efficacy in spinal muscular atrophy. Cell 185, 2057–2070 (2022).
pubmed: 35688133
doi: 10.1016/j.cell.2022.04.031
Darras, B. T. et al. Risdiplam-treated infants with type 1 spinal muscular atrophy versus historical controls. N. Engl. J. Med. 385, 427–435 (2021).
pubmed: 34320287
doi: 10.1056/NEJMoa2102047
Arechavala-Gomeza, V. et al. Comparative analysis of antisense oligonucleotide sequences for targeted skipping of exon 51 during dystrophin pre-mRNA splicing in human muscle. Hum. Gene Ther. 18, 798–810 (2007).
pubmed: 17767400
doi: 10.1089/hum.2006.061
Aartsma-Rus, A. et al. Development of exon skipping therapies for Duchenne muscular dystrophy: a critical review and a perspective on the outstanding issues. Nucleic Acid. Ther. 27, 251–259 (2017).
pubmed: 28796573
pmcid: 5649120
doi: 10.1089/nat.2017.0682
Koenig, M. et al. The molecular basis for duchenne versus becker muscular dystrophy: correlation of severity with type of deletion. Tha Am. J. Hum. Genet. 45, 498–506 (1989).
Wright, C. J., Smith, C. W. J. & Jiggins, C. D. Alternative splicing as a source of phenotypic diversity. Nat. Rev. Genet. https://doi.org/10.1038/s41576-022-00514-4 (2022).
doi: 10.1038/s41576-022-00514-4
pubmed: 35821097
Cunningham, F. et al. Ensembl 2019. Nucleic Acids Res. 47, D745–D751 (2019).
pubmed: 30407521
doi: 10.1093/nar/gky1113
Lewis, B. P., Green, R. E. & Brenner, S. E. Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans. Proc. Natl Acad. Sci. USA 100, 189–192 (2003).
pubmed: 12502788
doi: 10.1073/pnas.0136770100
Kovalak, C., Donovan, S., Bicknell, A. A., Metkar, M. & Moore, M. J. Deep sequencing of pre-translational mRNPs reveals hidden flux through evolutionarily conserved alternative splicing nonsense-mediated decay pathways. Genome Biol. 22, 132 (2021).
pubmed: 33941243
pmcid: 8091538
doi: 10.1186/s13059-021-02309-y
Keren, H., Lev-Maor, G. & Ast, G. Alternative splicing and evolution: diversification, exon definition and function. Nat. Rev. Genet. 11, 345–355 (2010).
pubmed: 20376054
doi: 10.1038/nrg2776
Ashraf, U., Benoit-Pilven, C., Lacroix, V., Navratil, V. & Naffakh, N. Advances in analyzing virus-induced alterations of host cell splicing. Trends Microbiol. 27, 268–281 (2019).
pubmed: 30577974
doi: 10.1016/j.tim.2018.11.004
Szakonyi, D. & Duque, P. Alternative splicing as a regulator of early plant development. Front. Plant. Sci. 9, 1174 (2018).
pubmed: 30158945
pmcid: 6104592
doi: 10.3389/fpls.2018.01174
Syed, N. H., Kalyna, M., Marquez, Y., Barta, A. & Brown, J. W. S. Alternative splicing in plants — coming of age. Trends Plant. Sci. 17, 616–623 (2012).
pubmed: 22743067
pmcid: 3466422
doi: 10.1016/j.tplants.2012.06.001
Godoy Herz, M. A. et al. Light regulates plant alternative splicing through the control of transcriptional elongation. Mol. Cell 73, 1066–1074 (2019).
pubmed: 30661982
doi: 10.1016/j.molcel.2018.12.005
Sanchez, S. E. et al. A methyl transferase links the circadian clock to the regulation of alternative splicing. Nature 468, 112–116 (2010).
pubmed: 20962777
doi: 10.1038/nature09470
Fairbrother, W. G., Yeh, R.-F., Sharp, P. A. & Burge, C. B. Predictive identification of exonic splicing enhancers in human genes. Science 297, 1007–1013 (2002).
pubmed: 12114529
doi: 10.1126/science.1073774